Synthesis and evaluation of homodimeric GnRHR antagonists having a rigid bis-propargylated benzene core

Bioorg Med Chem. 2008 Apr 1;16(7):3744-58. doi: 10.1016/j.bmc.2008.01.054. Epub 2008 Feb 2.

Abstract

The fact that GPCRs might function in a dimeric fashion is currently well accepted. For GnRHR, a GPCR that regulates gonadotropin release, there is evidence that the receptor also functions as a dimer. We here describe the design and synthesis of a set of dimeric GnRHR antagonists in order to understand the interaction of dimeric ligands to the receptor and to address the question whether GnRHR dimerization is a prerequisite for signalling. Biological evaluation of the compounds shows no discrimination between monomeric and dimeric-ligands in respect to binding affinities, however, the dimeric ligands appear to have different functional properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Benzene / chemical synthesis*
  • Benzene / chemistry
  • Benzene / pharmacology*
  • CHO Cells
  • Cell Survival / drug effects
  • Cricetinae
  • Cricetulus
  • Databases, Protein
  • Dimerization
  • Humans
  • Iodides / chemistry
  • Ligands
  • Molecular Structure
  • Pargyline / chemistry*
  • Receptors, LHRH / antagonists & inhibitors*
  • Receptors, LHRH / metabolism*
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Iodides
  • Ligands
  • Receptors, LHRH
  • Pargyline
  • Benzene